A novel method, based on the rational and systematic modulation
of macroscopic structural characteristics on a template originating
from a large number of natural, cell-lytic, amphipathic α-helical
peptides, was used to probe how the depths and shapes of hydrophobic
and polar faces and the conformational stability affect
antimicrobial activity and selectivity with respect to eukaryotic
cells. A plausible mode of action explaining the peptides’ behaviour
in model membranes, bacteria and host cells is proposed.
Cytotoxic activity, in general, correlated strongly with the hydrophobic
sector depth, and required a majority of aliphatic residue
side chains having more than two carbon atoms. It also correlated
significantly with the size of polar sector residues, which determines
the penetration depth of the peptide via the so-called
snorkel effect. Both an oblique gradient of long to short aliphatic
residues along the hydrophobic face and a stabilized helical
structure increased activity against host cells but not against bacteria,
as revealed by haemolysis, flow cytofluorimetric studies on
lymphocytes and surface plasmon resonance studies with model
phosphatidylcholine/cholesterol membranes. The mode of interaction
changes radically for a peptide with a stable, preformed
helical conformation compared with others that form a structure
only on membrane binding. The close correlation between effects
observed in biological andmodel systems suggests that the ‘carpet
model’ correctly represents the type of peptides that are bacteriaselective,
whereas the behaviour of those that lyse host cells is
more complex.
